EP1885724A1 - Heterocyclic spiro-compounds as aldosterone synthase inhibitors - Google Patents
Heterocyclic spiro-compounds as aldosterone synthase inhibitorsInfo
- Publication number
- EP1885724A1 EP1885724A1 EP06763351A EP06763351A EP1885724A1 EP 1885724 A1 EP1885724 A1 EP 1885724A1 EP 06763351 A EP06763351 A EP 06763351A EP 06763351 A EP06763351 A EP 06763351A EP 1885724 A1 EP1885724 A1 EP 1885724A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- compound
- alkylcarbonyl
- mmol
- heterocyclyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the invention relates to new heterocycles, to processes for preparing the compounds according to the invention, to pharmaceutical products comprising them, and to their use as active pharmaceutical ingredients, in particular as aldosterone synthase inhibitors.
- the present invention first provides compounds of the general formula
- W is C or, if Z is a bond and X is C, W is alternatively N;
- X is C or, if Z is a bond, X is alternatively N;
- Y is C or, if Z is C, Y is alternatively N;
- Z is C or a bond; the ring containing Y being maximum unsaturated;
- R is hydrogen, CrC 8 -alkyl, Ci-C 8 -alkoxy-Co-C 4 -alkyl, halogen, tri-C r C 4 -alkylsilyl, deuterium or trifluoromethyl;
- R 1 together with R 2 is a 5-14-membered carbocyclic or heterocyclic ring, which rings may be substituted by 1-4 CrC 8 -alkyl, Co-Cs-alkylcarbonyl, halogen, cyano-C 0 -C 6 -alkyl, oxo, trifluoromethyl, trifluoromethoxy, Co-Cs-alkylcarbonylamino, C 0 -C 8 -alkylcarbonyl-Ci-C 8 - alkylamino, carbamoyl, mono- and di-Ci-Cs-alkylaminocarbonyl, carboxy-C 0 -C 4 -alkyl, d-Cs-alkoxy, Ci-C 8 -alkoxycarbonyl, aryl, heterocyclyl, arylcarbonyl or heterocyclylcarbonyl, it being possible for aryl and heterocyclyl to be unsubstituted or substituted by 1-4 Cr
- the aryl term stands for an aromatic hydrocarbon which contains generally 5-14, preferably 6-10, carbon atoms and is for example phenyl, or naphthyl, e.g. 1- or 2-naphthyl. Preference is given to aryl having 6-10 carbon atoms, particularly phenyl or 1- or 2-naphthyl.
- the stated radicals may be unsubstituted or may be substituted one or more times, such as once or twice, in which case the substituent may be in any position, such as in the o, m or p position of the phenyl radical or in the 3 or 4 position of the 1- or 2-naphthyl radical, and there may also be two or more identical or different substituents.
- a 5-14-membered carbocyclic ring is a saturated or unsaturated, 5-8-membered, more preferably 6-membered, monocyclic ring system, a saturated or unsaturated, 9-11- membered, more 10-membered, bicyclic ring system and also a saturated or unsaturated, 7-14-membered tricyclic ring system.
- the stated radicals may be unsubstituted or may be substituted one or more times, such as once or twice, and there may also be two or more identical or different substituents.
- a saturated, monocyclic, carbocyclic , 4-8-membered ring is for example cyclohexyl.
- the heterocyclyl term stands for a saturated or unsaturated, 4-8-membered, more preferably 5-membered, monocyclic ring system, for a saturated or unsaturated, 7-12-membered, more preferably 9-10-membered, bicyclic ring system and also for a saturated or unsaturated, 7-12-membered tricyclic ring system, in each case containing an N, O or S atom in at least one ring, it also being possible for an additional N, O or S atom to be present in one ring, and the heteroatoms being separated preferably by at least one carbon atom.
- the stated radicals may be unsubstituted or may be substituted one or more times, such as once or twice, and there may also be two or more identical or different substituents.
- Unsaturated monocyclic heterocyclyl-C 0 -C 4 -alkyl is for example pyrrolyl, thiophenyl, thiazolyl or oxazolyl.
- Ci-C 8 -Alkyl can be linear or branched and/or bridged and is for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, tertiary-butyl, or a pentyl, hexyl or heptyl group.
- Ci-C 8 -Alkoxy is for example CrC 5 -alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary-butyloxy, tertiary-butyloxy or pentyloxy, but can also be a hexyloxy or heptyloxy group.
- Ci -C 8 -Al koxy-C 0 -C 4 -alkyl is for example, in addition to the definitions stated for CrC 8 -alkoxy, CrC 5 -alkoxy-Ci-C 4 -alkyl, such as methoxyethyl, ethoxyethyl, propyloxymethyl, isopropyloxy- butyl, butyloxymethyl, iso butyl oxyethyl, secondary-butyloxypropyl, tertiary-butyloxybutyl or pentyloxymethyl, but can also be a hexyloxymethyl or heptyloxymethyl group.
- Co-C 8 -Alkylcarbonyl is for example formyl, acetyl, propionyl, propylcarbonyl, isopropyl- carbonyl, butylcarbonyl, isobutylcarbonyl, secondary-butylcarbonyl or tertiary-butylcarbonyl.
- Cyano-C 0 -C 6 -alkyl may derive from linear or branched and/or bridged alkyl and is for example cyano, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 2-cyanoisopropyl, 4-cyanobutyl, 2-cyano- tertiary-butyl, or a cyanopentyl or cyanohexyl group.
- Co-C 8 -Alkylcarbonyl is for example formyl, acetyl, propionyl, propylcarbonyl, isopropyl- carbonyl, butylcarbonyl, isobutylcarbonyl, secondary-butylcarbonyl or tertiary-butylcarbonyl.
- Mono- or di-C r C 8 -alkylaminocarbonyl is for example C r C 4 -alkylaminocarbonyl, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl or butylaminocarbonyl, or - A -
- di-Ci-C 4 -alkylaminocarbonyl such as dimethylaminocarbonyl, N-methyl-N-ethylamino- carbonyl, diethylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N-methyl- aminocarbonyl.
- Co-Cs-Alkylcarbonyl-CrCs-alkylamino is for example formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, secondary- butylcarbonyl- or tertiary-butylcarbonyl-methylamino, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, secondary- butylcarbonyl- or tertiary-butylcarbonyl-ethylamino, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, secondary- butylcarbonyl
- Halogen is for example fluoro, chloro, bromo or iodo.
- Preferred compounds of the formula (I) are compounds of the general formulae
- R is very preferably hydrogen or deuterium.
- n is preferably a number 0 or 1.
- R is hydrogen or deuterium
- R 1 together with R 2 is cyclohexyl, decalinyl, pyrrolidinyl or pyranyl, which radicals may be substituted by 1-4 oxo, cyano-C o -C 6 -alkyl, C o -C 8 -alkylcarbonyl, heterocyclyl or heterocyclylcarbonyl, it being possible for heterocyclyl to be substituted by Ci-C 8 -alkyl, halogen, cyano or C o -C 8 -alkylcarbonyl.
- Particularly preferred compounds of the formula (I) are those of the general formulae (la'-ld 1 )
- the compounds of the formula (I) which possess at least one asymmetric carbon atom can exist in the form of optically pure enantiomers, mixtures of enantiomers, or racemates.
- Compounds having a second asymmetric carbon atom can exist in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, or mesocompounds.
- the invention embraces all of these forms.
- the compounds of the formula (la'-ld 1 ) have at least one asymmetric carbon atom, which is labelled "*".
- the compounds mentioned are to be understood as a single compound having a specific configuration around the designated asymmetric carbon atom. If a synthesis method is used which leads to racemic compounds, the racemate resolution is carried out in accordance with conventional methods, such as via a chiral HPLC column.
- Compounds of the formula (la'-ld') as described in the present invention exhibit a pronounced aldosterone synthase and/or 11- ⁇ -hydroxylase inhibitory activity.
- the aforementioned activity can, as the skilled worker is well aware and as described below, be comfortably determined via cellular assays based on the NCI-H295R human adrenocortical carcinoma cell line.
- compounds of the formula (la'-ld') have an activity which is at least 20 times better, but preferably 40 times better, than the substances of the formula (la'-ld') with the opposite configuration around the asymmetric carbon atom labelled "*".
- salts embraces salts with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulphonic acid, p-toluenesulphonic acid and the like.
- Salts of compounds containing salt- forming groups are, in particular, acid addition salts, salts with bases or else, if appropriate, if two or more salt-forming groups are present, are mixed salts or inner salts.
- the compounds of the formula (I) can be prepared analogously to preparation processes known from the literature. Details of the specific preparation variants can be found from the examples.
- the compounds of the formula (I) can also be prepared in optically pure form. Separation into antipodes is possible by methods known per se, either, preferably, at an early stage in synthesis, by salt formation with an optically active acid such as, for example, (+)- or (-)- mandelic acid and separation of the diastereomeric salts by fractional crystallization, or, preferably, at a fairly late stage, by derivatization with a chiral auxiliary component, such as, for example, (+)- or (-)-camphanyl chloride and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bond to the chiral auxiliary.
- the pure diastereomeric salts and derivatives can be analysed to determine the absolute configuration of the compound present, using customary spectroscopic methods, with single-c
- methyl-, ethyl-, diethyl- or triethylamine mono-, bis- or tris(2-hydroxy-lower alkyl)amines, such as ethanolamine, diethanolamine or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tertiary- butylamine, N,N-di-lower alkyl-N-(hydroxy-lower alkyl)amine, such as N,N-di-N-dimethyl-N- (2-hydroxyethyl)amine, or N-methyl-D-glucamine, or quaternary ammonium hydroxides, such as tetrabutylammonium hydroxide.
- the compounds of the formula (I) containing a basic group, such as amino group can form acid addition salts, with suitable inorganic acids for example, such as hydrohalic acid, such as hydrochloric acid, hydrobromic acid, or sulphuric acid with replacement of one or both protons, phosphoric acid with replacement of one or more protons, orthophosphoric acid or metaphosphoric acid for example, or pyrophosphoric acid with replacement of one or more protons, or with organic carboxylic, sulphonic or phosphonic acids or N-substituted sulphamic acids, examples being acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid
- Isolation and purification can also be carried out using pharmaceutically unsuitable salts.
- ester derivatives which are converted by solvolysis in physiological medium into the original carboxylic acid, such as, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters, such as lower ⁇ -(amino, mono- or dialkylamino, carboxyl, lower alkoxycarbonyl)- alkyl esters or such as lower ⁇ -(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl)alkyl esters; pivaloyloxymethyl esters and similar esters are conventionally used as ester derivatives of this kind.
- a defined compound in this invention also includes its prodrug derivative and salt form, insofar as this is possible and appropriate.
- Aldosterone is a steroidal hormone which is synthesized in the zona glomerulosa cells of the adrenal cortex by the enzyme aldosterone synthase (CYP11B2). Aldosterone production and secretion is regulated by the adrenocorticotropic hormone (ACTH), angiotensin II, potassium and sodium ions.
- ACTH adrenocorticotropic hormone
- the primary biological function of aldosterone is the regulation of the salt balance, with aldosterone controlling the reabsorption of sodium ions from the renal filtrate and the secretion of potassium ions into the renal filtrate.
- aldosterone secretion also called hyperaldosteronism
- hyperaldosteronism The state of excessive aldosterone secretion, also called hyperaldosteronism, can lead to high blood pressure, hypokalaemia, alkalosis, muscle weakness, polyuria, polydipsia, edemas, vasculitis, increased collagen formation, fibrosis and endothelial dysfunction.
- the chemical compounds described in this invention inhibit the cytochrome P450 enzyme aldosterone synthase (CYP11 B2) and can therefore be used to treat states induced by aldosterone.
- the compounds described can be employed for preventing, delaying the progression of or treating states such as hypokalaemia, hypertension, congestive heart failure, acute and - in particular - chronic renal failure, cardiovascular restenosis, atherosclerosis, metabolic syndrome (syndrome X), adiposity (obesity), vasculitis, primary and secondary hyperaldosteronism, proteinuria, nephropathy, diabetic complications, such as diabetic nephropathy, myocardial infarction, coronary heart disease, increased collagen formation, fibrosis, vascular and coronary tissue changes (remodelling) secondary to high blood pressure, endothelial dysfunction, and oedemas secondary to sclerosis, nephrosis and congestive heart failure.
- states such as hypokalaemia, hypertension,
- Cushing's syndrome may come about on the one hand as a result of Cortisol hypersynthesis, which may be generated by an adrenocortical tumour, or on the other hand as the consequence of excessive stimulation of the adrenal cortex by ACTH.
- the first form is referred to as primary hypercortisolism
- the second form as secondary hypercortisolism.
- An excessive and persistent Cortisol secretion may also accompany a stress response, which can lead to depression, hyperglycaemia and the suppression of the immune system.
- the compounds can be employed in states such as ectopic ACTH syndrome, the change in adrenocortical mass, primary pigmented nodular adrenocortical disease (PPNAD) and Carney complex (CNC), anorexia nervosa, chronic alcohol poisoning, nicotine or cocaine withdrawal syndrome, post-traumatic stress syndrome, cognitive impairment after a stroke, and cortisol-induced mineralocorticoid excess.
- states such as ectopic ACTH syndrome, the change in adrenocortical mass, primary pigmented nodular adrenocortical disease (PPNAD) and Carney complex (CNC), anorexia nervosa, chronic alcohol poisoning, nicotine or cocaine withdrawal syndrome, post-traumatic stress syndrome, cognitive impairment after a stroke, and cortisol-induced mineralocorticoid excess.
- the cell line NCI-H295R was originally isolated from an adrenocortical carcinoma and has been characterized in the literature through the stimulable secretion of steroid hormones and the presence of the enzymes essential for steroidogenesis.
- the NCI-H295R cells have Cyp11A (cholesterol side-chain cleavage), Cyp11B1 (steroid 11 ⁇ -hydroxylase), Cyp11 B2 (aldosterone synthase), Cyp17 (steroid 17 ⁇ -hydroxylase and/or 17,20-lyase), Cyp19 (aromatase), Cyp21 B2 (steroid 21 -hydroxylase) and 3 ⁇ -HSD (hydroxysteroid dehydrogenase).
- the cells show the physiological property of zonally undifferentiated human foetal adrenocortical cells which, however, have the capacity to produce the steroid hormones which are formed in the three, phenotypically distinguishable zones in the adult adrenal cortex.
- the NCI-H295R cells (American Type Culture Collection, ATCC, Rockville, MD, USA) are grown in Dulbecco's Modified Eagle'Ham F-12 Medium (DME/F12) which has been supplemented with Ultroser SF Serum (Soprachem, Cergy-Saint-Christophe, France), insulin, transferrin, selenite (I-T-S, Becton Dickinson Biosciences, Franklin Lakes, NJ, USA) and antibiotics in 75 cm 2 cell culture vessels at 37 0 C and in a 95% air - 5% carbon dioxide atmosphere. The cells are subsequently transferred for colony formation into a 24-well incubation vessel.
- DME/F12 Dulbecco's Modified Eagle'Ham F-12 Medium
- I-T-S insulin
- Becton Dickinson Biosciences Franklin Lakes, NJ, USA
- DME/F12 medium which is now supplemented with 0.1% bovine serum albumin instead of Ultroser SF, for 24 hours.
- the experiment is initiated by cultivating the cells in DME/F12 medium which is supplemented with 0.1% bovine serum albumin and test compound, in the presence or absence of cell stimulants, for 72 hours.
- the test substance is added in a concentration range from 0.2 nanomolar to 20 millimolar.
- Cell stimulants which can be used are angiotensin Il (10 or 100 nanomolar), potassium ions (16 millimolar), forskolin (10 micromolar) or a combination of two stimulants.
- the IC 50 values for active test compounds are ascertained by a simple linear regression analysis in order to construct inhibition plots without data weighting.
- the inhibition plot is calculated by fitting a 4-parameter logistic function to the raw data points using the least squares method.
- the equation of the 4-parameter logistic function is calculated as follows:
- the compounds of the present invention show inhibitory effects at minimum concentrations of about 10 ⁇ 3 to about 10 ⁇ 10 mol/l in the in vitro systems.
- An alternative method for stimulating aldosterone synthesis is for adult male, catheterized Wistar rats, weighing between 250 and 350 grams, to be subjected to a low-salt diet for 48 hours and additionally be treated 16 hours, and possibly with additional repetition 2 hours, before the start of the experiment with 10 mg/kg furosemide, administered subcutaneously or intraperitoneally. Pilot studies showed that this pretreatment increases the plasma aldosterone level by 5 to 20-fold over a period of 12-24 hours.
- the catheters are chronically implanted into the animals' carotid and thus permit periodic blood sampling of a volume of up to 0.2 ml using an AccuSampler (DiLab Europe, Lund, Sweden).
- the experiment starts with the oral administration of the test substances in a dose range of 0.01 - 10 mg/kg.
- the blood samples are taken with the AccuSampler 1 hour before administration of the test substances and subsequently after 2, 4, 6, 8, 12, 16 and 24 hours.
- the blood samples are anticoagu- lated with heparin and centrifuged.
- the reduction in damage to the heart through the inhibition of aldosterone synthase with compounds described herein can be shown in vivo by the following protocol.
- the protocol corresponds in large part to the publication (Rocha et al, Endocrinology, Vol. 141 , pp 3871- 3878, 2000).
- Rats are housed individually and receive freely available drinking water which contains 0.9% sodium chloride during the experiment. Three days later, the animals are subjected to one of the three following treatments. Group I (control group of 8 animals) is treated for 14 days with the chemical L-NAME (N-nitro-L-arginine methyl ester, Sigma, St. Louis, MO, USA) which inhibits nitric-oxide synthase. On day 11 of this treatment, an osmotic minipump charged with sodium chloride solution is subcutaneously implanted into each animal. Group Il (L-NAME/Angll of 8 animals) is treated with L-NAME for 14 days.
- L-NAME N-nitro-L-arginine methyl ester
- an osmotic minipump charged with angiotensin Il (Angll) solution is subcutaneously implanted into each animal.
- Group III L-NAM E/Ang I I/test substance of 8 animals
- the test substance is for this purpose dissolved in distilled water and administered orally by gavage.
- Groups I and Il receive only the vehicle without test substance.
- the experiment is stopped on day 14 of L-NAME treatment.
- L-NAME is administered in a concentration of 60 mg/100 mL in the 0.9% NaCI drinking water, leading to a daily intake of about 60 mg/kg.
- Angiotensin Il is administered by means of an Alzet osmotic minipump (model 2001 ; Alza Corp, Palo Alto, CA). The minipump is implanted sub- cutaneously in the back of the neck.
- Angiotensin Il (human and with a peptide purity of 99%) is purchased from Sigma Chemical Co., St. Louis, MO and administered in a dose of 225 ⁇ g/kg/day in sodium chloride solution.
- the concentration of angiotensin Il for charging the pumps is calculated on the basis of: a) the average pumping rate stated by the manufacturer; b) the body weight of the animals on the day before implantation of the pumps; and c) the planned dose.
- the rats are sacrificed on day 14.
- the hearts are removed and the ventricles/atria are sliced like a "loaf of bread" in order to obtain three samples from the following approximate regions of the heart: superior, middle and inferior.
- the samples are fixed in 10% buffered formalin. Paraffin sections are cut and stained with hematoxylin/eosin. The sections are assessed by a single scientist unaware of the assignment to groups.
- One section from each region of the heart is analysed for each rat. Specific parts of the heart (left and right ventricle, and the septum) are evaluated separately.
- the whole section is examined histologically for myocardial damage (irrespective of severity) manifested by myocyte necrosis, inflammatory cells, haemorrhages and general tissue damage.
- the histological data are assessed on the basis of a comparison of groups Il and III, i.e. angiotensin Il with and without test substance. Evaluation of the samples can take place semiquantitatively and be represented in the form of
- mice 4-week old, male doubly transgenic rats (dTGR), which overexpress both human angiotensinogen and human renin and consequently develop hypertension.
- Age-matched Sprague-Dawley (SD) rats serve as non-hypertensive control animals.
- the animals are divided into treatment groups and receive test substance or vehicle (control) each day for 3-4 weeks. Throughout the study, the animals receive standard feed and tap water ad libitum.
- the systolic and diastolic blood pressure, and the heart rate are measured telemetrically by means of implanted transducers, allowing the animals free and unrestricted movement.
- the animals are placed once a week in metabolism cages in order to determine the 24-hour urinary excretion of albumin.
- Heart dimensions (left ventricular mass, end-diastolic diameter and wall thickness, septum thickness, shortening fraction) and diastolic filling are measured by echocardiography at the start and at the end of the treatment under isoflurane anaesthesia (M mode recording in the short axis and tissue Doppler imaging by means of a commercial echocardiography instrument which is equipped with a 15 MHz probe).
- M mode recording in the short axis and tissue Doppler imaging by means of a commercial echocardiography instrument which is equipped with a 15 MHz probe.
- the animals are sacrificed and the kidneys and hearts are removed for determining the weight and for immunohistological investigations (fibrosis, macrophage
- the compounds of the present invention can be administered orally or enterally, such as, for example, intravenously, intraperitoneally, intramuscularly, rectally, subcutaneously or else by direct injection of the active substance locally into tissues or tumours.
- patient encompasses warmblooded species and mammals such as, for example, human, primate, bovine, dog, cat, horse, sheep, mouse, rat and pig.
- the compounds can be administered as pharmaceutical product or be incorporated into an administration device which ensures sustained release of the compound.
- the amount of substance to be administered can vary over a wide range and represent every effective dose.
- the dose of the effective substance each day can be between about 0.005 and 50 milligrams per kilogram of body weight, but is preferably between about 0.05 and 5 milligrams per kilogram of body weight each day.
- the compounds can be formulated in solid or liquid pharmaceutical forms such as, for example, as capsules, pills, tablets, coated tablets, granules, powders, solutions, suspensions or emulsions.
- the dose of a solid pharmaceutical form can be one usual hard gelatin capsule which may be filled with active ingredients and excipients such as lubricants and fillers, such as, for example, lactose, sucrose and maize starch.
- Another form of administration may be represented by tableting of the active substance of the present invention.
- the tableting can take place with conventional tableting excipients such as, for example, lactose, sucrose, maize starch, combined with binder from gum acacia, maize starch or gelatin, disintegrants such as potato starch or crosslinked polyvinylpyrrolidone (PVPP) and lubricants such as stearic acid or magnesium stearate.
- conventional tableting excipients such as, for example, lactose, sucrose, maize starch, combined with binder from gum acacia, maize starch or gelatin, disintegrants such as potato starch or crosslinked polyvinylpyrrolidone (PVPP) and lubricants such as stearic acid or magnesium stearate.
- excipients suitable for soft gelatin capsules are vegetable oils, waxes, fats, semisolid and liquid polyols etc.
- excipients suitable for producing solutions and syrups are water, polyols, sucrose, invert sugar, glucose etc.
- the compounds can be formulated in solid or liquid pharmaceutical forms such as, for example, suppositories.
- excipients suitable for suppositories are natural or hardened oils, waxes, fats, semiliquid or liquid polyols etc.
- the compounds can be formulated as injectable dosage of the active ingredient in a liquid or suspension.
- the preparations usually comprise a physiologically tolerated sterile solvent which may comprise a water-in-oil emulsion, with or without surfactant, and other pharmaceutically acceptable excipients.
- Oils which can be used for such preparations are paraffins and triglycerides of vegetable, animal or synthetic origin, such as, for example, peanut oil, soya oil and mineral oil.
- injectable solutions generally comprise liquid carriers such as, preferably, water, saline, dextrose or related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol.
- the substances may be administered as transdermal patch system, as depot injection or implant if the formulation makes sustained delivery of the active ingredient possible.
- the active substance can be compressed as granules or to narrow cylinders and be administered subcutaneously or intramuscularly as depot injection or implant.
- the pharmaceutical products may in addition also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, aromatizing agents, salts to change the osmotic pressure, buffers, coating agents or antioxidants. They may also comprise other therapeutically valuable substances too.
- the compounds of the invention described herein permit the following methods of use: - as therapeutic combination in the form of a product or of a kit which is composed of individual components consisting of a compound described herein, in free form or as pharmaceutically useful salt, and at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, an antidiabetic, an obesity-reducing or a lipid-lowering effect, which can be used either simultaneously or sequentially.
- the product and the kit may comprise instructions for use.
- one or more blood pressure-lowering active ingredients as such for example: renin inhibitors such as aliskiren; angiotensin Il receptor blockers such as candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan etc.;
- ACE inhibitors such as quinapril, ramipril, trandolapril, lisinopril, captopril, enalapril etc.
- calcium antagonists such as nifedipine, nicardipine, verapamil, isradipine, nimodipine, amlodipine, felodipine, nisoldipine, diltiazem, fendiline, flunarizine, perhexiline, gallopamil etc.
- diuretics such as hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, etacrynic acid, furosemide, indacrinone, metolazone, triamterene, chlortalidone, etc.
- aldosterone receptor blockers such as spironolactone, eplerenone
- PAC plasma aldosterone level
- PRC plasma renin concentration
- a diagnostic test system which permits quantitative determination of the plasma renin activity (PRA, plasma renin activity)
- PRA plasma renin activity
- a diagnostic test system which permits quantitative determination of the plasma aldosterone / renin level (ARC, aldosterone renin concentration)
- ARC plasma aldosterone / renin concentration
- a diagnostic test system which permits quantitative determination of the plasma aldosterone / renin activity (ARR, aldosterone to renin activity ratio)
- a diagnostic test system which permits quantitative determination of the plasma
- diagnosis-therapy combinations can be used separately or in products which comprise a plurality of components.
- the starting material is prepared as follows: a) 7,8-Dihvdro-5'H,6H-spiro ⁇ midazori ,5-alpyridine-5,3'-pyrrolidinl-5'-one
- a solution of 378.000 mmol of diisopropylamine in 180 ml of tetrahydrofuran is admixed dropwise at -78°C with 179.000 mmol of n-butyllithium (1.6M in hexane).
- the yellowish solution is stirred at -20°C for 30 minutes then cooled again to -78°C.
- This solution is admixed dropwise at -78°C with a solution of 126.000 mmol of 1 -benzyl piperidine-2,6- dicarbonitrile [98195-08-5] and 138.600 mmol of hexamethylphosphorictriamide in 50 ml of tetrahydrofuran.
- the starting material is prepared as follows: a) 7,8-Dihvdro-6H-spiro ⁇ midazori ,5-alpyridine-5,3'-pyrrolidinel
- reaction solution is subsequently stirred at room temperature for an hour and then added dropwise at 0 0 C to a solution of 1 mmol of Z. ⁇ -dihydro- ⁇ H-spirotimidazoti.S-aJpyridine-S.S'-pyrrolidine] (Example 3a) and 2 mmol of triethylamine in 5 ml of dichloromethane.
- the reaction mixture is subsequently stirred at room temperature for 3 hours, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3x). The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO 2 60F) on the basis of the Rf value.
- the resulting suspension is heated at 100°C for 24 hours. After the end of reaction the mixture is concentrated and from the residue the title compound is identified by means of flash chromatography (SiO 2 60F) on the basis of the Rf value.
- the starting materials are prepared as follows:
- the title compound is obtained by a method analogous to that described in Example 1a and 1 b, starting from C-(2-benzyl-2,7-diazaspiro[4.5]dec-6-yl)methylamine, and identified on the basis of the Rf value.
- reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane.
- the combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO 2 60F) on the basis of the Rf value.
- a solution of 5 mmol of tert-butyl 2-benzyl-6-methylene-2,7-diazaspiro[4.5]decane-7-carboxylate in 60 ml of tetrahydrofuran is admixed at 0°C with 10.6 mmol of 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran).
- the reaction solution is stirred at 60 0 C for 15 hours and then cooled to room temperature.
- the solution is admixed with 50 ml each of 3M sodium hydroxide solution and 30% hydrogen peroxide.
- the reaction mixture is stirred at room temperature for 2 hours.
- a solution of 1 mmol of S-ethoxycarbonylmethyl ⁇ -oxo-piperidine-S-carboxylic acid ethyl ester, 1 mmol of calcium chloride, and 5 ml of methanol is cooled to 0 0 C and treated with one portion of 1 mmol of sodium borohydride, keeping the temperature at 0 - 5°C with cooling for 2 hours.
- the mixture is allowed to warm to room temperature overnight.
- the solids are filtered and washed with methanol.
- the methanol filtrate is concentrated.
- the residue is triturated with diethyl ether and decanted.
- the residue is treated with water and the separated solid is filtered and washed with water.
- the aqueous filtrates are saturated with potassium carbonate and extracted with dichloromethane (3X) methylene chloride.
- reaction mixture is then cooled to -78°C and transferred (via cannula) to a solution of 5 mmol of freshly prepared lithium diisopropyl-amide in 20 ml of dry tetrahydrofuran at -78°C.
- a solution of 5 mmol of freshly prepared lithium diisopropyl-amide in 20 ml of dry tetrahydrofuran at -78°C After stirring for 30 minutes at -78°C, 5.25 mmol of 2-bromoacetic acid ethyl ester [105-36-2] are added drop wise and stirring is continued for 1 hour while the solution is allowed to warm to 0 0 C.
- the reaction is quenched by addition of aqueous saturated ammonium chloride solution and extracted with diethyl ether (3x). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO 2 60F) on the basis of the
- the starting materials are prepared as follows: a) 6,7-Dihvdro-2'H,5H-spiro ⁇ midazori ,5-alpyridine-8,5'-ri ,31oxazolidinl-2'-one A solution of 1.00 mmol of ⁇ -aminomethyl-S.ey. ⁇ -tetrahydroimidazoti.S-aJpyridin- ⁇ -ol in 5 ml of tetrahydrofuran is admixed with 1.00 mmol of N,N'-carbonyldiimidazole. The reaction solution is heated at reflux for 15 hours and then evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO 2 60F) and identified on the basis of the Rf value.
- SiO 2 60F flash chromatography
Abstract
Description
Claims
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Families Citing this family (133)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR056888A1 (en) * | 2005-12-09 | 2007-10-31 | Speedel Experimenta Ag | HIDEROCICLIL IMIDAZOL DERIVATIVES |
TW200813071A (en) | 2006-04-12 | 2008-03-16 | Speedel Experimenta Ag | Spiro-imidazo compounds |
WO2007140385A2 (en) * | 2006-05-31 | 2007-12-06 | Abbott Laboratories | Thiazole compounds as cannabinoid receptor ligands and uses thereof |
US8841334B2 (en) * | 2006-05-31 | 2014-09-23 | Abbvie Inc. | Compounds as cannabinoid receptor ligands and uses thereof |
WO2007140439A2 (en) * | 2006-05-31 | 2007-12-06 | Abbott Laboratories | Compounds as cannabinoid receptor ligands and uses thereof |
WO2008121558A1 (en) | 2007-03-28 | 2008-10-09 | Abbott Laboratories | 1, 3-thiazol-2 (3h) -ylidene compounds as cannabinoid receptor ligands |
WO2008119744A1 (en) * | 2007-03-29 | 2008-10-09 | Novartis Ag | Heterocyclic spiro-compounds |
US7872033B2 (en) * | 2007-04-17 | 2011-01-18 | Abbott Laboratories | Compounds as cannabinoid receptor ligands |
US8501794B2 (en) * | 2007-04-17 | 2013-08-06 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
JP2010527929A (en) * | 2007-05-18 | 2010-08-19 | アボット・ラボラトリーズ | Novel compounds as cannabinoid receptor ligands |
US9193713B2 (en) * | 2007-10-12 | 2015-11-24 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
CA2716857A1 (en) | 2008-03-11 | 2009-09-17 | Teodozyi Kolasa | Novel compounds as cannabinoid receptor ligands |
ES2397764T3 (en) | 2008-04-01 | 2013-03-11 | Abbott Gmbh & Co. Kg | Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy |
US20100035919A1 (en) * | 2008-08-05 | 2010-02-11 | Abbott Laboratories | Compounds useful as inhibitors of protein kinases |
EP2331516B1 (en) | 2008-08-15 | 2013-03-13 | Abbott Laboratories | Imine derivatives as cannabinoid receptor ligands |
US8846730B2 (en) | 2008-09-08 | 2014-09-30 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
US8859596B2 (en) * | 2008-09-16 | 2014-10-14 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
WO2010045402A1 (en) * | 2008-10-17 | 2010-04-22 | Abbott Laboratories | Trpv1 antagonists |
TW201020236A (en) * | 2008-10-17 | 2010-06-01 | Abbott Lab | TRPV1 antagonists |
US20100160322A1 (en) | 2008-12-04 | 2010-06-24 | Abbott Laboratories | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
US8557983B2 (en) | 2008-12-04 | 2013-10-15 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
UA108193C2 (en) | 2008-12-04 | 2015-04-10 | APOPTOZINDUCE FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTO-IMMUNE DISEASES | |
US8563735B2 (en) | 2008-12-05 | 2013-10-22 | Abbvie Inc. | Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
HUE029289T2 (en) | 2008-12-05 | 2017-02-28 | Abbvie Inc | Sulfonamide derivatives as bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
US8586754B2 (en) | 2008-12-05 | 2013-11-19 | Abbvie Inc. | BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
PA8854001A1 (en) * | 2008-12-16 | 2010-07-27 | Abbott Lab | NEW COMPOUNDS AS CANABINOID RECEIVERS LIGANDS |
SG172393A1 (en) | 2009-01-19 | 2011-07-28 | Abbott Lab | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
DK2511264T3 (en) | 2009-01-19 | 2015-06-22 | Abbvie Inc | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
AR075442A1 (en) | 2009-02-16 | 2011-03-30 | Abbott Gmbh & Co Kg | AMINOTETRALINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USES IN THERAPY |
TW201038569A (en) | 2009-02-16 | 2010-11-01 | Abbott Gmbh & Co Kg | Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy |
TWI519530B (en) * | 2009-02-20 | 2016-02-01 | 艾伯維德國有限及兩合公司 | Carboxamide compounds and their use as calpain inhibitors |
ES2540119T3 (en) * | 2009-03-27 | 2015-07-08 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
US8236822B2 (en) * | 2009-03-27 | 2012-08-07 | Abbott Laboratories | Compounds as cannabinoid receptor ligands |
CA2756178A1 (en) * | 2009-03-27 | 2010-09-30 | Abbott Laboratories | Compounds as cannabinoid receptor ligands |
EP2243479A3 (en) | 2009-04-20 | 2011-01-19 | Abbott Laboratories | Novel amide and amidine derivates and uses thereof |
US8236798B2 (en) | 2009-05-07 | 2012-08-07 | Abbott Gmbh & Co. Kg | Carboxamide compounds and their use as calpain inhibitors |
US20220315555A1 (en) | 2009-05-26 | 2022-10-06 | Abbvie Inc. | Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases |
US8546399B2 (en) | 2009-05-26 | 2013-10-01 | Abbvie Inc. | Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases |
US9034875B2 (en) | 2009-05-26 | 2015-05-19 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
PE20120345A1 (en) | 2009-05-26 | 2012-05-17 | Abbvie Bahamas Ltd | DERIVATIVES OF 2- (1H-PIRROLO [2,3-B] PYRIDIN-5-ILOXI) -N-FENYLSULFONYLBENZAMIDE AS INHIBITORS OF ANTI-APOPTOTIC PROTEINS |
KR101442897B1 (en) | 2009-05-28 | 2014-09-23 | 노파르티스 아게 | Substituted aminopropionic derivatives as neprilysin inhibitors |
AR076706A1 (en) | 2009-05-28 | 2011-06-29 | Novartis Ag | AMINOBUTIRIC DERIVATIVES REPLACED AS NEPRILISINE INHIBITORS |
US8962639B2 (en) * | 2009-05-29 | 2015-02-24 | Abbvie Inc. | Potassium channel modulators |
US20110095033A1 (en) | 2009-10-28 | 2011-04-28 | Belkin International, Inc. | Portable Multi-Media Communication Device Protective Carrier and Method of Manufacture Therefor |
JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors |
JP2013512241A (en) | 2009-11-25 | 2013-04-11 | アボット・ラボラトリーズ | Potassium channel modulator |
TW201130855A (en) * | 2009-12-16 | 2011-09-16 | Abbott Lab | Prodrug compounds useful as cannabinoid ligands |
JP5959501B2 (en) | 2010-03-25 | 2016-08-02 | アッヴィ・インコーポレイテッド | Apoptosis inducers for the treatment of cancer and immune and autoimmune diseases |
TWI520960B (en) | 2010-05-26 | 2016-02-11 | 艾伯維有限公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
WO2011159785A1 (en) | 2010-06-15 | 2011-12-22 | Abbott Laboratories | Novel compounds as cannabinoid receptor ligands |
CN103140476A (en) | 2010-08-10 | 2013-06-05 | Abbvie公司 | Novel trpv3 modulators |
US9045459B2 (en) | 2010-08-13 | 2015-06-02 | AbbVie Deutschland GmbH & Co. KG | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9051280B2 (en) | 2010-08-13 | 2015-06-09 | AbbVie Deutschland GmbH & Co. KG | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8883839B2 (en) | 2010-08-13 | 2014-11-11 | Abbott Laboratories | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8846743B2 (en) | 2010-08-13 | 2014-09-30 | Abbott Laboratories | Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8877794B2 (en) | 2010-08-13 | 2014-11-04 | Abbott Laboratories | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9266855B2 (en) | 2010-09-27 | 2016-02-23 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
UA113500C2 (en) | 2010-10-29 | 2017-02-10 | MEL EXTRUSION SOLID DISPERSIONS CONTAINING AN APOPTOSIS-INDUCING AGENT | |
KR20180059560A (en) | 2010-10-29 | 2018-06-04 | 애브비 인코포레이티드 | Solid dispersions containing an apoptosis-inducing agent |
WO2012059432A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | N-phenyl-(homo)piperazinyl-benzenesulfonyl or benzenesulfonamide compounds suitable for treating disorders that respond to the modulation of the 5-ht6 receptor |
WO2012059431A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor |
CN103313968A (en) | 2010-11-15 | 2013-09-18 | Abbvie公司 | Nampt and rock inhibitors |
CA2817093A1 (en) | 2010-11-15 | 2012-05-24 | Abbvie Inc. | Nampt inhibitors |
WO2012067822A1 (en) | 2010-11-16 | 2012-05-24 | Abbott Laboratories | Pyrazolo [1, 5 -a] pyrimidin potassium channel modulators |
US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
US8609674B2 (en) | 2010-11-16 | 2013-12-17 | Abbvie Inc. | Potassium channel modulators |
RU2628560C2 (en) | 2010-11-23 | 2017-08-18 | Эббви Инк. | Salts and crystalline forms of apottosis-inducing agent |
DK2642999T3 (en) | 2010-11-23 | 2017-01-09 | Abbvie Ireland Unlimited Co | METHODS OF TREATMENT FOR USING selectivity-VE BCL-2 INHIBITORS |
US9090592B2 (en) | 2010-12-30 | 2015-07-28 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
US8802693B1 (en) | 2011-03-09 | 2014-08-12 | Abbvie Inc. | Azaadamantane derivatives and methods of use |
US9012651B2 (en) | 2011-03-24 | 2015-04-21 | Abbvie Inc. | TRPV3 modulators |
WO2012134943A1 (en) | 2011-03-25 | 2012-10-04 | Abbott Laboratories | Trpv1 antagonists |
US9309200B2 (en) | 2011-05-12 | 2016-04-12 | AbbVie Deutschland GmbH & Co. KG | Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8859549B2 (en) | 2011-05-13 | 2014-10-14 | Abbvie, Inc. | Potassium channel modulators |
RU2609200C2 (en) | 2011-07-08 | 2017-01-30 | Новартис Аг | Method of treating atherosclerosis in individuals with high level of triglycerides |
MX2014001457A (en) | 2011-08-05 | 2014-08-21 | Abbvie Deutschland | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquin oline derivatives, pharmaceutical compositions containing them, and their use in therapy. |
TWI571466B (en) | 2011-10-14 | 2017-02-21 | 艾伯維有限公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
TWI561521B (en) | 2011-10-14 | 2016-12-11 | Abbvie Inc | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
WO2013062964A2 (en) | 2011-10-24 | 2013-05-02 | Abbvie Inc. | Novel trpv3 modulators |
US20130116241A1 (en) | 2011-11-09 | 2013-05-09 | Abbvie Inc. | Novel inhibitor compounds of phosphodiesterase type 10a |
WO2013072520A1 (en) | 2011-11-18 | 2013-05-23 | AbbVie Deutschland GmbH & Co. KG | N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8969325B2 (en) | 2011-12-19 | 2015-03-03 | Abbvie Inc. | TRPV1 antagonists |
US8859584B2 (en) | 2011-12-19 | 2014-10-14 | Abbvie, Inc. | TRPV1 antagonists |
US9365512B2 (en) | 2012-02-13 | 2016-06-14 | AbbVie Deutschland GmbH & Co. KG | Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
WO2013149376A1 (en) | 2012-04-02 | 2013-10-10 | Abbott Laboratories | Chemokine receptor antagonists |
EP2838881B1 (en) | 2012-04-20 | 2018-08-08 | AbbVie Inc. | Isoindolone derivatives |
CN104428301A (en) | 2012-05-11 | 2015-03-18 | 艾伯维公司 | NAMPT inhibitors |
MX2014013758A (en) | 2012-05-11 | 2015-02-05 | Abbvie Inc | Thiazolecarboxamide derivatives for use as nampt inhibitors. |
MX2014013752A (en) | 2012-05-11 | 2014-12-08 | Abbvie Inc | Nampt inhibitors. |
CA2873097A1 (en) | 2012-05-11 | 2013-11-14 | Todd M. Hansen | Pyridazine and pyridine derivatives as nampt inhibitors |
US20130317055A1 (en) | 2012-05-24 | 2013-11-28 | Abbvie Inc. | Neuronal nicotinic agonist and methods of use |
US20130317054A1 (en) | 2012-05-24 | 2013-11-28 | Abbvie Inc. | Neuronal nicotinic agonist and methods of use |
BR112014031068A2 (en) | 2012-06-12 | 2017-06-27 | Abbvie Inc | pyridinone and pyridazinone derivatives |
US8796328B2 (en) | 2012-06-20 | 2014-08-05 | Abbvie Inc. | TRPV1 antagonists |
IN2015DN02070A (en) | 2012-09-14 | 2015-08-14 | Abbvie Deutschland | |
US20140080813A1 (en) | 2012-09-14 | 2014-03-20 | AbbVie Deutschland GmbH & Co. KG | Tricyclic quinoline and quinoxaline derivatives |
UY35144A (en) | 2012-11-20 | 2014-06-30 | Novartis Ag | APELINE SYNTHETIC LINEAR MIMETICS FOR THE CARDIAC INSUFFICIENCY TREATMENT |
MX367525B (en) | 2013-02-14 | 2019-08-26 | Novartis Ag | Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors. |
BR112015021549A2 (en) | 2013-03-13 | 2017-07-18 | Abbvie Inc | pyridine kinase cdk9 inhibitors |
AU2014244263A1 (en) | 2013-03-13 | 2015-08-13 | Abbvie Inc. | CDK9 kinase inhibitors |
JP2016512560A (en) | 2013-03-14 | 2016-04-28 | アッヴィ・インコーポレイテッド | Pyrrolopyrimidine CDK9 kinase inhibitor |
US20140275082A1 (en) | 2013-03-14 | 2014-09-18 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
CN105339366A (en) | 2013-03-14 | 2016-02-17 | 艾伯维德国有限责任两合公司 | Oxindole derivatives carrying an oxetane substituent and use thereof for treating vasopressine-related diseases |
WO2014151444A1 (en) | 2013-03-14 | 2014-09-25 | Abbvie Inc. | Pyrrolo[2,3-b]pyridine cdk9 kinase inhibitors |
AU2014231567A1 (en) | 2013-03-14 | 2015-10-01 | Abbvie Inc. | Pyrrolo[2,3-b]pyridine CDK9 kinase inhibitors |
MX2015012008A (en) | 2013-03-14 | 2016-04-15 | Abbvie Deutschland | Novel inhibitor compounds of phosphodiesterase type 10a. |
US9656955B2 (en) | 2013-03-15 | 2017-05-23 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9650334B2 (en) | 2013-03-15 | 2017-05-16 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
UY35670A (en) | 2013-07-25 | 2015-02-27 | Novartis Ag | CYCLIC POLYPEPTIDES FOR THE TREATMENT OF HEART FAILURE |
BR112016001376A2 (en) | 2013-07-25 | 2017-10-24 | Novartis Ag | synthetic apelin polypeptide bioconjugates |
AU2014336154A1 (en) | 2013-10-17 | 2016-04-28 | AbbVie Deutschland GmbH & Co. KG | Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy |
SG11201602982YA (en) | 2013-10-17 | 2016-05-30 | Abbvie Deutschland | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9840495B2 (en) | 2013-12-20 | 2017-12-12 | AbbVie Deutschland GmbH & Co. KG | Oxindole derivatives carrying a piperidyl-substituted azetidinyl substituent and use thereof for treating vasopressine-related diseases |
US9328112B2 (en) | 2014-02-06 | 2016-05-03 | Abbvie Inc. | Tetracyclic CDK9 kinase inhibitors |
EP3191459A1 (en) | 2014-09-05 | 2017-07-19 | AbbVie Deutschland GmbH & Co. KG | Fused heterocyclic or carbocyclic compounds carrying a substituted cycloaliphatic radical and use thereof for treating vasopressin-related diseases |
US9550754B2 (en) | 2014-09-11 | 2017-01-24 | AbbVie Deutschland GmbH & Co. KG | 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy |
MX2017009534A (en) | 2015-01-23 | 2018-04-10 | Novartis Ag | Synthetic apelin fatty acid conjugates with improved half-life. |
WO2016160938A1 (en) | 2015-04-02 | 2016-10-06 | Abbvie Inc. | N-(1,3-thiazol-2-yl)pyrimidine-5-carboxamides as trpv3 modulators |
US20180339996A1 (en) | 2015-11-25 | 2018-11-29 | AbbVie Deutschland GmbH & Co. KG | Hexahydropyrazinobenz- or -pyrido-oxazepines carrying an oxygen-containing substituent and use thereof in the treatment of 5-ht2c-dependent disorders |
MX2018013573A (en) | 2016-05-07 | 2019-08-01 | Shanghai Fochon Pharmaceutical Co Ltd | Certain protein kinase inhibitors. |
JOP20190086A1 (en) | 2016-10-21 | 2019-04-18 | Novartis Ag | Naphthyridinone derivatives and their use in the treatment of arrhythmia |
US11168078B2 (en) | 2016-11-28 | 2021-11-09 | Shanghai Fochon Pharmaceutical Co., Ltd. | Sulfoximine, sulfonimidamide, sulfondiimine and diimidosulfonamide compounds as inhibitors of indoleamine 2,3-dioxygenase |
EP3601255A1 (en) | 2017-03-21 | 2020-02-05 | AbbVie Deutschland GmbH & Co. KG | Proline amide compounds and their azetidine analogues carrying a specifically substituted benzyl radical |
SI3612531T1 (en) | 2017-04-18 | 2022-11-30 | Shanghai Fochon Pharmaceutical Co., Ltd. | Apoptosis-inducing agents |
UY38072A (en) | 2018-02-07 | 2019-10-01 | Novartis Ag | COMPOSITIONS DERIVED FROM BUTANOIC ESTER SUBSTITUTED WITH BISPHENYL AS INHIBITORS OF NEP, COMPOSITIONS AND COMBINATIONS OF THE SAME |
JP7294677B2 (en) | 2018-03-14 | 2023-06-20 | フォチョン・ファーマシューティカルズ・リミテッド | Substituted (2-azabicyclo[3.1.0]hexane-2-yl)pyrazolo[1,5-a]pyrimidine compounds and substituted (2-azabicyclo[3.1.0]hexane-2 as TRK kinase inhibitors -yl)imidazo[1,2-b]pyridazine compounds |
US11485707B2 (en) | 2018-03-23 | 2022-11-01 | Fochon Pharmaceuticals, Ltd. | Deuterated compounds as rock inhibitors |
CN113166101A (en) | 2018-11-27 | 2021-07-23 | 诺华股份有限公司 | Cyclic pentameric compounds as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders |
UY38485A (en) | 2018-11-27 | 2020-06-30 | Novartis Ag | CYCLIC TETRAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN / KEXIN TYPE 9 (PCSK9) INHIBITORS, METHOD OF TREATMENT, USE AND PREPARATION |
US20220024981A1 (en) | 2018-11-27 | 2022-01-27 | Novartis Ag | Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders |
TW202333563A (en) | 2021-11-12 | 2023-09-01 | 瑞士商諾華公司 | Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder |
AR127698A1 (en) | 2021-11-23 | 2024-02-21 | Novartis Ag | NAFTYRIDINOONE DERIVATIVES FOR THE TREATMENT OF A DISEASE OR DISORDER |
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JPH0971586A (en) * | 1995-09-07 | 1997-03-18 | Yamanouchi Pharmaceut Co Ltd | New bicyclic condensed imidazole derivative |
MXPA02010091A (en) | 2000-04-12 | 2003-02-12 | Novartis Ag | Combination of organic compounds. |
ES2270143T3 (en) * | 2002-08-07 | 2007-04-01 | Novartis Ag | ORGANIC COMPOUNDS AS AGENTS FOR THE TREATMENT OF CONDITIONS MEDIATED BY ALDOSTERONE. |
ATE398124T1 (en) | 2002-11-18 | 2008-07-15 | Novartis Pharma Gmbh | IMIDAZOÄ1,5ÜA PYRIDINE DERIVATIVES AND METHODS FOR TREATING ALDOSTERONE-ASSOCIATED DISEASES |
TW200716634A (en) * | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Heterocyclic spiro-compounds |
TW200716105A (en) * | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Imidazole compounds |
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WO2006128853A1 (en) | 2006-12-07 |
CN101184757A (en) | 2008-05-21 |
ATE471939T1 (en) | 2010-07-15 |
PT1885724E (en) | 2010-07-29 |
US8071773B2 (en) | 2011-12-06 |
PL1885724T3 (en) | 2010-11-30 |
ES2347978T3 (en) | 2010-11-26 |
EP1885724B1 (en) | 2010-06-23 |
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